PROJECT SUMMARY Medulloblastoma is the most common malignant pediatric brain tumor. Although surgical resection and radiotherapy are effective at eliminating some forms of medulloblastoma, more aggressive tumors do not respond to any treatment. In addition, patients who respond to classical treatment often suffer from cognitive deficits. Thus, new drugs and drug combinations need to be developed to effectively treat medulloblastoma. Essential to identifying medulloblastoma drugs is validating therapeutic targets. We propose here that CK1? and BRD4 are possible therapeutic targets in medulloblastoma. CK1? is a kinase essential for various signaling pathways while BRD4 is an epigenetic reader protein that controls expression of several oncogenes. We now demonstrate that CK1? directly phosphorylates BRD4 to target it to chromatin in granule cell progenitors, one of the principle cells in the brain that can give rise to medulloblastoma. We demonstrate that this is a previously unappreciated means of CK1? controlling the Sonic Hedgehog (SHH) pathway, which is dysregulated in several cancers including medulloblastoma. As BRD4 recruitment to chromatin is necessary for its activity, inhibiting CK1? may reduce BRD4 dependent transcription of oncogenes in medulloblastoma. We will determine the contribution of CK1? to BRD4 recruitment to chromatin in medulloblastoma (Aim 1). To examine the contribution of CK1? and BRD4 to SHH-dependent medulloblastoma progression, we will assess whether CK1? or BRD4 deletion increases survival of mice bearing activation of the SHH pathway (Aim 2). Furthermore, we will determine whether CK1? and BRD4 inhibition via small molecules reduces tumor burden in mouse models of medulloblastoma (Aim 3). Collectively, our studies will validate the BRD4-CK1? pathway as a therapeutic target in medulloblastoma and identify possible therapies for SHH dependent tumors.